Posts Tagged ‘drugs’

Researchers from St. Jude Children’s Research Hospital have discovered that inhibiting an enzyme called cyclin-dependent kinase 2 (CDK2) protects mice and rats from noise- or drug-induced hearing loss. The study, which will be published March 7 in the Journal of Experimental Medicine, suggests that CDK2 inhibitors prevent the death of inner ear cells, which has the potential to save the hearing of millions of people around the world.

According to the World Health Organization, 360 million people worldwide, including 32 million children, suffer from hearing loss caused by congenital defects or other factors. These factors include infectious disease, use of certain medicines, or exposure to excessive noise. Yet, there are currently no FDA-approved drugs to prevent or treat hearing loss.

A team of researchers led by Dr. Jian Zuo screened over 4,000 drugs for their ability to protect cochlear cells from the chemotherapy agent cisplatin. Cisplatin is used to treat a variety of cancers but causes irreversible hearing loss in up to 70% of patients.

Zuo and colleagues identified multiple compounds that protected cochlear cells from cisplatin, several of which are already approved to treat other conditions. Three of the ten most effective compounds were inhibitors of an enzyme called CDK2. One of these CDK2 inhibitors, kenpaullone, was more effective than four other compounds that are currently in clinical trials for treating hearing loss.

Injecting kenpaullone into the middle ear protected both mice and rats from cisplatin-induced hearing loss. Moreover, kenpaullone also protected the hearing of mice to noise as loud as 100 dB. “Given that 100-dB noise is in the range of noise insults commonly experienced by people in our society, kenpaullone could have significant clinical application in treating noise-induced hearing loss,” says Zuo.

In the case of cisplatin-induced hearing loss, kenpaullone appears to protect hair cells by preventing CDK2 from stimulating the production of toxic reactive oxygen species from the cells’ mitochondria.

“The robust protection conferred by one-time local delivery of kenpaullone suggests that CDK2 inhibitors may transform the clinical prevention and treatment of cisplatin- and noise-induced hearing loss in patients,” Zuo says. “Modifications of the treatment regimens, additional optimization of the delivery methods via the use of hydrogels, and structural modifications of the compounds via medicinal chemistry could ensure even better results with CDK2 inhibitors in treating hearing loss in humans.”

For years, scientists have known that mitochondria—the power source of cells—play a role in brain disorders such as depression, bipolar disorder, anxiety and stress responses. But recently scientists at the University of Maryland School of Medicine (UMSOM) have identified significant mitochondrial changes in brain cells that take place in cocaine addiction, and they have been able to block them.

In mice exposed repeatedly to cocaine, UMSOM researchers were able to identify an increase in a molecule that plays a role in mitochondria division (or fission) in a reward region of the brain. Researchers were able to block this change by using a special chemical, Mdivi-1. The researchers also blocked responses to cocaine by genetically manipulating the fission molecule within the mitochondria of brain cells, according to research published in Neuron.

“We are actually showing a new role for mitochondria in cocaine-induced behavior, and it’s important for us to further investigate that role,” said Mary Kay Lobo, PhD, Associate Professor of Anatomy and Neurobiology.

The researchers initially studied the mitochondria in cocaine-exposed mice and determined that mitochondria fission increased in the major reward region of the brain. To confirm this same change in humans, researchers were able to identify similar changes in the mitochondrial fission molecule in tissue collected from post mortem individuals who were cocaine dependents.

Dr. Lobo said that this latest research could help UMSOM researchers better understand changes in brain cells and mitochondria from other addictive disorders. “We are interested to see if there are mitochondrial changes when animals are taking opiates. That is definitely a future direction for the lab,” she said.

“This research is another great example of our ground-breaking work at the University of Maryland School of Medicine to better understand the biology behind drug addiction,” said E. Albert Reece, MD, PhD, MBA, University Executive Vice President of Medical Affairs and the John Z. and Akiko K. Bowers Distinguished Professor and Dean at the University of Maryland School of Medicine.

Scientists at The Scripps Research Institute (TSRI) have achieved a major milestone toward designing a safe and effective vaccine to both treat heroin addiction and block lethal overdose of the drug. Their research, published today in the journal Molecular Pharmaceutics, shows how a new anti-heroin formulation that is safe in animal models remains stable at room temperature for at least 30 days. As a result, the vaccine is close to being ready for human testing.

“The heroin vaccine is one step closer to clinical evaluation,” says Candy S. Hwang, PhD, first author of the study and a research associate at TSRI.

According to the National Institute on Drug Abuse, 15,446 Americans died from heroin overdose between 2000 and 2016, and the mortality rates are increasing. Heroin abuse has been further fueled by a rise in prescription opioid abuse—studies show that opioid pain reliever users are 40 times more likely to abuse heroin.

The first formulation of the heroin vaccine was developed in 2013 by a team led by Kim D. Janda, PhD, the Ely R. Callaway Jr. Professor of Chemistry and member of the Skaggs Institute for Chemical Biology at TSRI. It has been shown to be effective—and safe—in both mouse and non-human primate models.

The vaccine works by training the immune system antibodies to recognize and bind to heroin molecules, blocking the drug from reaching the brain to cause a “high.” Researchers believe that blocking the high of heroin will help eliminate the motivation for many recovering addicts to relapse into drug use.

The heroin molecule does not naturally prompt an antibody response, so researchers attach it to a carrier protein that alerts the immune system to start making antibodies. Scientists also add an ingredient called an adjuvant to the vaccine, which boosts the immune response and makes the vaccine more effective.

Hwang says, “Our goal was to prepare a vaccine that could be advanced to clinical trials. As such, we were looking for the best combination of ‘hapten’ (the heroin molecule), carrier protein and adjuvant to keep the vaccine both stable for transport and storage but still efficacious.”

For the new study, the researchers investigated how 20 different carrier protein/adjuvant combinations worked, including shelf stability based on temperature and storage time and whether the formulation was a liquid or powder.

Their experiments in rodent models showed that the best vaccine formulation contained a carrier protein called tetanus toxoid (TT) and adjuvants called alum and CpG ODN. The discovery that alum worked best as an adjuvant was especially significant since alum is one of the few adjuvants used in vaccines already approved by the U.S. Food and Drug Administration. The researchers also found that there was no difference in how well it worked between the liquid and powder versions of this formulation.

Hwang notes that the best vaccine formulation showed protection against lethal doses of heroin. This is particularly important as many heroin addicts have succumb to overdose and death during their attempts to quit the drug.

With this new study, the researchers have shown that the vaccine is safe and effective in animal models, stable under clinical conditions and reliant on an already-approved adjuvant. The next step is to find a producer to make the vaccine on a large scale.

“We believe that a heroin vaccine would be tremendously beneficial for people who have a heroin substance use disorder but have found difficulty in trying to quit,” says Hwang.

In addition to Hwang and Janda, authors of the study, “Enhancing Efficacy and Stability of an Anti-Heroin Vaccine: Examination of Antinociception, Opioid Binding Profile, and Lethality,” were Paul T. Bremer, Cody J. Wenthur, Beverly Ellis and Bin Zhou of The Scripps Research Institute; and Sam On Ho, SuMing Chiang and Gary Fujii of Molecular Express, Inc.

The study was supported by the National Institutes of Health (grants UH3DA041146, F32AI126628, F32DA043323, R42DA040422 and R44AI094770).

Fans of the herb kratom say it offers pain relief, calms anxiety, and can help ease opioid withdrawal symptoms. However, a new report from the Food and Drug Administration says the popular herbal substance acts like a prescription-strength opioid and is associated with several dozen deaths.

What exactly is this polarizing botanical drug?

What is kratom?
Kratom is a tropical tree (Mitragyna speciosa) related to coffee that is native to Southeast Asia. Leaves from the tree have been used for centuries as a traditional remedy for pain.

The leaves can be eaten raw, but are usually crushed and made into a powder. The powder is then consumed in capsules, smoked or brewed in teas.

According to the U.S. Drug Enforcement Administration, consumption of kratom in low doses produces simulating effects. However, in large amounts it acts as a sedative, and can lead to psychotic symptoms, as well as psychological and physiological dependence.

Why there is concern
The DEA includes kratom on its Drugs of Concern list (substances that aren’t regulated by the Controlled Substances Act, but that could pose risks to people who abuse them), and the National Institute of Drug Abuse has identified kratom as an emerging drug of abuse.

Between 2010 and 2015, the Centers for Disease Control and Prevention noted a tenfold increase in calls about kratom to poison control centers across the U.S., from 26 to 263. About 42 percent of those cases involved non-life-threatening symptoms that required some treatment. About 7 percent were classified as major and life-threatening.

In the February 2018 report, FDA Commissioner Scott Gottlieb, M.D. said, “There is no evidence to indicate that kratom is safe or effective for any medical use. And claiming that kratom is benign because it’s ‘just a plant’ is shortsighted and dangerous. After all, heroin is an illegal, dangerous, and highly-addictive substance containing the opioid morphine, derived from the seed pod of the various opium poppy plants.”

Gottleib warned of potential side effects including changes in neurologic and cardiovascular function. He also cited 44 reported deaths “associated with the use of kratom.”

Consumer Reports points out other possible dangers associated with kratom:

Kratom has been found to be laced with opioids, including tramadol and hydrocodone.
There’s little research about drug interactions, and users are mixing kratom with legal and illegal drugs, which can be dangerous.
Some users who have turned to kratom to kick an opioid addiction have become hooked on kratom instead.
It kratom legal?
In 2016, the DEA announced plans to list kratom as a Schedule 1 substance, which would add it to the ranks of LSD, heroin, marijuana and ecstasy. The plan would have essentially banned kratom, but the DEA changed course and instead gave the public a chance to comment.

Now, the substance is mostly legal in the U.S., depending on where you live. According to the American Kratom Association, several cities, counties and seven states (Alabama, Arkansas, Indiana, Rhode Island, Tennessee, Vermont and Wisconsin) and the District of Columbia have banned or seriously restricted the use of kratom.

While supporters are working hard to keep kratom legal, the DEA and detractors argue that the substance is not safe.

“We’ve learned a tragic lesson from the opioid crisis,” Gottleib said. “That we must pay early attention to the potential for new products to cause addiction and we must take strong, decisive measures to intervene.”

For centuries, musicians have used drugs to enhance creativity and listeners have used drugs to heighten the pleasure created by music. And the two riff off each other, endlessly. The relationship between drugs and music is also reflected in lyrics and in the way these lyrics were composed by musicians, some of whom were undoubtedly influenced by the copious amounts of heroin, cocaine and “reefer” they consumed, as their songs sometimes reveal.

Acid rock would never have happened without LSD, and house music, with its repetitive 4/4 beats, would have remained a niche musical taste if it wasn’t for the wide availability of MDMA (ecstasy, molly) in the 1980s and 1990s.

And don’t be fooled by country music’s wholesome name. Country songs make more references to drugs than any other genre of popular music, including hip hop.

Under the influence

As every toker knows, listening to music while high can make it sound better. Recent research, however, suggests that not all types of cannabis produce the desired effect. The balance between two key compounds in cannabis, tetrahydrocannabinol and cannabidiols, influence the desire for music and its pleasure. Cannabis users reported that they experienced greater pleasure from music when they used cannabis containing cannabidiols than when these compounds were absent.

Listening to music – without the influence of drugs – is rewarding, can reduce stress (depending upon the type of music listened to) and improve feelings of belonging to a social group. But research suggests that some drugs change the experience of listening to music.

Clinical studies that have administered LSD to human volunteers have found that the drug enhances music-evoked emotion, with volunteers more likely to report feelings of wonder, transcendence, power and tenderness. Brain imaging studies also suggest that taking LSD while listening to music, affects a part of the brain leading to an increase in musically inspired complex visual imagery.

Certain styles of music match the effects of certain drugs. Amphetamine, for example, is often matched with fast, repetitive music, as it provides stimulation, enabling people to dance quickly. MDMA’s (ecstasy) tendency to produce repetitive movement and feelings of pleasure through movement and dance is also well known.

An ecstasy user describes the experience of being at a rave:

“I understood why the stage lights were bright and flashing, and why trance music is repetitive; the music and the drug perfectly complemented one another. It was as if a veil had been lifted from my eyes and I could finally see what everyone else was seeing. It was wonderful.”

There is a rich representation of drugs in popular music, and although studies have shown higher levels of drug use in listeners of some genres of music, the relationship is complex. Drug representations may serve to normalise use for some listeners, but drugs and music are powerful ways of strengthening social bonds. They both provide an identity and a sense of connection between people. Music and drugs can bring together people in a political way, too, as the response to attempts to close down illegal raves showed.

People tend to form peer groups with those who share their own cultural preferences, which may be symbolised through interlinked musical and substance choices. Although there are some obvious synergies between some music and specific drugs, such as electronic dance music and ecstasy, other links have developed in less obvious ways. Drugs are one, often minor, component of a broader identity and an important means of distinguishing the group from others.

Although it is important not to assume causality and overstate the links between some musical genres and different types of drug use, information about preferences is useful in targeting and tailoring interventions, such as harm reduction initiatives, at music festivals.

In USC’s lecture halls, labs and executive offices, Dr. Carmen A. Puliafito was a towering figure. The dean of the Keck School of Medicine was a renowned eye surgeon whose skill in the operating room was matched by a gift for attracting money and talent to the university.

There was another side to the Harvard-educated physician.

During his tenure as dean, Puliafito kept company with a circle of criminals and drug users who said he used methamphetamine and other drugs with them, a Los Angeles Times investigation found.

Puliafito, 66, and these much younger acquaintances captured their exploits in photos and videos. The Times reviewed dozens of the images.

Shot in 2015 and 2016, they show Puliafito and the others partying in hotel rooms, cars, apartments and the dean’s office at USC.

In one video, a tuxedo-clad Puliafito displays an orange pill on his tongue and says into the camera, “Thought I’d take an ecstasy before the ball.” Then he swallows the pill.

In another, Puliafito uses a butane torch to heat a large glass pipe outfitted for methamphetamine use. He inhales and then unleashes a thick plume of white smoke. Seated next to him on a sofa, a young woman smokes heroin from a piece of heated foil.

As dean, Puliafito oversaw hundreds of medical students, thousands of professors and clinicians, and research grants totaling more than $200 million. He was a key fundraiser for USC, bringing in more than $1 billion in donations, by his estimation.

Puliafito resigned his $1.1-million-a-year post in March 2016, in the middle of the spring term, saying he wanted to explore outside opportunities.

Three weeks earlier, a 21-year-old woman had overdosed in his presence in a Pasadena hotel room. The woman was rushed to a hospital, where she recovered. Police found methamphetamine in the hotel room, according to a police report, but made no arrests. Puliafito has never spoken publicly about the incident, which is being reported here for the first time.

After he stepped down as dean, USC kept Puliafito on the medical school faculty, and he continues to accept new patients at campus eye clinics, according to Keck’s website. He also is a central witness in a $185-million lawsuit in which the University of California has accused USC of misconduct in its hiring away of a star researcher.

Puliafito did not respond to interview requests or written questions. Reached by phone last week, he hung up without commenting after hearing a brief summary of The Times’ reporting.

Earlier, in an email he sent to the newspaper shortly after resigning as dean, Puliafito said he made the move voluntarily in order to pursue a biotech job.

“Bottom line, I was dean for almost a decade. It was great, but I was ready and open to jumping on these opportunities when they came along,” he wrote.

USC President C.L. Max Nikias and Provost Michael Quick, who was Puliafito’s boss, did not respond to repeated requests for information about the circumstances surrounding Puliafito’s resignation. Nor did the university press office.

When reporters visited Nikias’ office to ask about the former dean, his chief of staff, Dennis Cornell, told them: “The president will not be speaking to The Times on this matter.”

The Times interviewed six people who partied with Puliafito in Pasadena, Huntington Beach and Las Vegas, as well as at USC. They ranged in age from late teens to late thirties. None were USC students.

One, Sarah Warren, was the woman who overdosed in the Pasadena hotel room. She told The Times she met Puliafito in early 2015 while working as a prostitute. She said they were constant companions for more than a year and a half, and that Puliafito used drugs with her and sometimes brought her and other members of their circle to the USC campus after hours to party.

Puliafito has no known criminal record, and public records show no blemishes on the medical licenses he holds in California and three other states. A review of court records in those states found no malpractice claims against him.

He is highly regarded in the field of ophthalmology and regularly addresses doctors at national conventions and training seminars. Over the last decade, he has coauthored more than 60 medical journal articles on retinal disease and other topics. Since 2008, he has served on the governing board of the California Institute of Regenerative Medicine, the state agency that oversees stem cell research.

It was a tip about the incident in the Pasadena hotel that led The Times to discover Puliafito’s other life.

Just before 5 p.m. on March 4, 2016, an employee of the Hotel Constance, an upscale Colorado Boulevard landmark, called 911 to report that a guest had suffered an apparent overdose.

The hotel employee transferred a Fire Department dispatcher to a third-floor room. A man answered, identified himself as a doctor and said his companion’s condition was not serious, according to a recording of the call.

“My girlfriend here had a bunch of drinks and she’s sleeping,” he told the dispatcher. Asked whether the woman had taken anything else, he replied, “I think just the alcohol.”

After the ambulance arrived, another hotel employee placed a 911 call to ask that police be sent, too.

“I got somebody in one of the rooms, they [were] doing drugs in the room,” the employee told an emergency operator, according to the 911 recording. He added, “I think they [were] doing crystal meth.”

Paramedics took the woman to Huntington Memorial Hospital. Authorities did not release her name. The Times identified her as Warren through interviews, social media and property records.

Warren, now 22, has been in an Orange County drug treatment program since November, and said she no longer has contact with Puliafito. She talked about their relationship in a series of interviews.

She said she and Puliafito had been partying at the hotel for two days. Then she “took too much GHB” — gamma-hydroxybutyrate, the so-called date-rape drug that some users take in lower doses for its euphoric effect. Warren said the drug left her “completely incapacitated.”

After she awoke in the hospital six hours later, Puliafito picked her up, and “we went back to the hotel and got another room and continued the party,” she said.

The videos reviewed by The Times are consistent with Warren’s account.

A recording made the night before the overdose shows Puliafito and Warren in a room at the hotel. Warren asks him to help her crush methamphetamine in preparation for doing a “hot rail,” a method of snorting the drug.

“Absolutely,” Puliafito replies. Warren is later shown bending over a tray with several lines of white powder.

In a separate video of Puliafito and Warren, recorded at another hotel about a day after her overdose, she blames the Hotel Constance episode on GHB.

“Carmen saved my life,” she says on the video.

Puliafito is seen with what appears to be a meth pipe in his hand and, later, in his mouth.

Sources with access to these and other videos and photos of Puliafito allowed The Times to view the images on the condition they not be published.

A week after the hotel overdose, a witness filed an anonymous complaint through a city website urging Pasadena authorities to investigate Puliafito and the police handling of the incident, according to a copy of the complaint obtained through the California Public Records Act.

Three days later, the same witness phoned the office of USC president Nikias and told two employees about Puliafito’s role in the hotel incident. The witness spoke to The Times on the condition of anonymity.

Phone records confirm that the witness made a six-minute call to Nikias’ office on March 14, 2016, 10 days after the overdose.

A week and a half later, Puliafito resigned as dean.

Concerned that Pasadena police were not investigating, the witness then approached The Times. The newspaper asked the Police Department for its report on the overdose.

Initially, a department spokeswoman said there was no report, apart from a call-for-service log. After The Times made repeated requests for additional information, the department acknowledged that an officer at the scene should have prepared a report. The officer was ordered to do so in June 2016 — three months after the incident.

In the report, Puliafito is identified as a witness to the overdose and a “friend” of the victim. The rest of the document is heavily redacted.

The department also released an evidence report that shows officers seized a little over a gram of methamphetamine from the hotel room. The name of the drug’s “owner” is redacted, and the Pasadena address listed as that person’s residence does not exist.

Under state law, possession of methamphetamine could be charged as a misdemeanor. Asked why no one was charged, Pasadena police spokeswoman Tracey Ibarra said officers would have had to determine who was “responsible” for the drugs. She declined to answer questions about the extent of the officers’ investigation. Warren said they never interviewed her.

Although Puliafito told the 911 operator he thought his companion was under the influence of alcohol alone, Ibarra said the woman was “obviously under the influence of narcotics — the same narcotics that were in the room.”

Ten years ago, USC went looking for a transformational leader for its medical program. U.S. News & World Report, in its annual report on the best American medical schools, ranked Keck 25 spots below UCLA in research. That was too low for USC leaders, who saw a top-rated medical school as crucial to their national aspirations. They needed a dean who could deliver the money and marquee researchers to make Keck an elite institution.

“Someone who could take a great school and make it even better,” then-USC President Steven Sample said at the close of the 2007 search process. “We found that person in Dr. Carmen Puliafito.”

Puliafito, a native of Buffalo, N.Y., who graduated magna cum laude from Harvard Medical School, had helped invent a laser technology — optical coherence tomography — that revolutionized the way doctors around the world diagnose and treat eye disease.

He had a track record of building institutions and raising their profiles. At Tufts University Medical School in Boston in the 1990s, Puliafito was founding director of the New England Eye Center. A complimentary 1993 profile in the Boston Globe described Puliafito’s “in your face” personality and likened him to “one of those Yellowstone Park mud pots: placid on the surface for a few minutes, then erupting for a moment, then calm again.”

Puliafito left Tufts to serve as director of the University of Miami’s Bascom Palmer Eye Institute from 2001 to 2007. There, he presided over a doubling of faculty and tripling of research funding, according to school news releases.

His time at Miami was not trouble-free. Marc Brockman, an optometrist at the institute, filed a lawsuit against Puliafito in 2006 for assault and battery and accused the university of negligence in hiring him.

Brockman alleged in sworn testimony that Puliafito, in a profane “tantrum” over an inoperable piece of medical equipment, grabbed him by the collar of his lab coat and choked him.

Puliafito denied wrongdoing.

During the case, it emerged that the university had investigated separate complaints of sexual harassment against Puliafito, according to sworn testimony and court filings in the lawsuit. The records do not reveal the outcome of the investigation, and a university spokeswoman said in response to questions about the probe: “We don’t have anything to provide.”

Puliafito and the university reached a confidential settlement with Brockman in June 2007.

Two months later, USC hired Puliafito.

When Warren first met Puliafito in early 2015 she was a 20-year-old college dropout who had recently moved out of her parents’ Huntington Beach home and was advertising on an escort website.

She offered him meth, she said, and he accepted. She said it was clear he was comfortable around drugs.

Warren said that after that first encounter, they began seeing each other regularly.

After a few weeks, she said, she Googled his name and learned that he was USC’s medical school dean.

“I thought, ‘This is wild,’” she recalled.

The images viewed by The Times reflect an easy familiarity between Warren and Puliafito. In the video that shows him smoking from a large glass pipe while she heats a piece of foil and inhales, Warren calls Puliafito “Tony,” short for Anthony, his middle name.

Looking into the camera, Warren says she and Puliafito are making a “good old-fashioned doing-drugs video” to send to a friend.

Law enforcement officials who watched the video at The Times’ request said that what it showed was consistent with smoking meth and heroin.

In another video, Warren takes a drag from a meth pipe, and as she exhales, Puliafito inhales the smoke from her mouth, a technique known as “shotgunning.”

In a separate series of photos, Warren sits on Puliafito’s lap as she smokes meth.

Puliafito rented apartments for her in Huntington Beach and near his home in Pasadena so she would always be available, she said. He gave her spending money and covered her legal bills, she said.

During their time together, Warren was arrested four times on charges that include drug possession, drunk driving and petty theft, court records show. She pleaded guilty or no contest in each case and was placed on probation, given community service or ordered to pay fines.

She said Puliafito told her he was taking care of her, but she came to view the money he gave her as “a trap.”

“It was never enough for me to save up and leave,” she said.

She said it seemed odd that someone with Puliafito’s responsibilities could devote so much time to her. She said he would spend the night with her in apartments or hotel rooms he paid for, leave early in the morning to go to his home and then return to her with breakfast.

“He was always with me,” she said. “It was as if he had nothing else to do.”

In these circles, Puliafito presented himself as an architect of USC’s rising reputation as a research institution. When asked about his extracurricular pursuits, he mentioned his award-winning stamp collection and spending time with his wife, a Harvard classmate, and three adult children.

Don Stokes was not part of that world.

Stokes, 39, is an Orange County karaoke deejay with multiple convictions for drug possession. Contacted by The Times, Stokes said that Warren introduced him to Puliafito, and that they would spend hours drinking and using drugs in bars and hotel rooms with a group that included addicts and prostitutes.

Stokes said Puliafito gave him meth, including while he was living at New Life Spirit, a Huntington Beach sober home for recovering addicts. Warren said she saw it happen.

Stokes said that Puliafito seemed to believe that showering the group with cash and gifts was a way of “tying into this generation.”

“He would say, ‘Money is not an issue,’” recalled Stokes, who recently completed another stint in rehab. “There was hardly a day when he wasn’t around.”

Another member of the group was Kyle Voigt, 37, an Iraq war veteran with a criminal record that dates to at least 2009 and includes convictions for possession of heroin for sale.

The Times reviewed numerous photos and videos of Voigt and Puliafito with other members of their circle.

A series of September 2015 photos show Voigt and Warren in Puliafito’s office at the USC health sciences campus. The time stamp indicates the photos were taken around 3 a.m.

In one shot, Warren, wearing a USC shirt, stands next to Puliafito’s desk. A portrait of the dean and his wife is visible, and framed Dodgers and Red Sox jerseys can be seen on the wall.

In another photo, Voigt is wearing an inflatable Trojan hat and a white Keck School lab coat embroidered with the dean’s name. Both he and Warren are holding pieces of aluminum foil with darkened patches in the middle. The Times showed the image to law enforcement officials, who said the patches were consistent with the marks left by smoking heroin. In the photo, Warren has a lighter in her hand.

Other photos, shot the same year at a Pasadena gas station, show Voigt at the wheel of Puliafito’s vintage Mercedes, with the dean seated in the rear. Voigt is holding a piece of foil in his lap.

At one in a string of court appearances in 2015, he was asked to provide his address on a legal form. He listed Puliafito’s residence, a $5-million Tudor Revival mansion in Pasadena.

In a brief interview this spring at the L.A. County jail, where he was being held on suspicion of identity theft, Voigt declined to explain why he provided Puliafito’s address as his own and would not discuss whether he used drugs with the doctor.

He did say that Puliafito frequently socialized with him, Warren and other young people.

“Carmen’s always there,” he said.

Puliafito twice scheduled visits to the jail to see Voigt, although records show the visits were canceled. On a May 13, 2016, reservation form, Puliafito said he had a “professional” relationship with the inmate.

On a Feb. 16, 2017, form, he described himself as a “friend.”

Warren said her younger brother was part of the group that hung out with Puliafito and used drugs with him.

Charles Warren, who lives with his parents in Huntington Beach, confirmed his sister’s account. He said in an interview that he was 17 and had little experience with drugs, beyond marijuana, when his sister introduced him to Puliafito in the spring of 2015.

Sarah and Charles Warren said Puliafito wrote them prescriptions for asthma inhalers to soothe lungs raw from smoking marijuana and methamphetamine. Charles Warren, now 19, provided The Times a copy of a CVS prescription history, dated Dec. 30, 2015, for an Advair inhaler that shows Puliafito as the prescribing physician and Charles Warren as the patient.

In early 2016, about a year after she first met Puliafito, Sarah Warren sought help for her drug problem. She spent time in two different rehab programs, and completed the second one, at Michael’s House in Palm Springs, in February 2016.

Less than three weeks later, she and Puliafito checked into the Hotel Constance in Pasadena.

On a sunny afternoon in June 2016, dozens of Puliafito’s colleagues gathered on a lawn at USC’s health sciences campus for a catered reception in his honor. It had been three months since he’d announced his resignation, and the school’s top administrators took turns lauding his accomplishments as head of the medical school.

Keck had climbed in national medical school rankings: U.S. News & World Report ranked it 31st in research last year, seven rungs higher than when Puliafito became dean.

“Today, we have one of the, not just the area’s, but the nation’s preeminent medical schools and medical enterprises — and, in many ways, thanks to the leadership of Carmen,” Nikias told the crowd.

Key to Keck’s rise in stature was Puliafito’s ability to headhunt the type of big-name researchers who brought grant money and prestige. He recruited more than 70 professors to Keck, according to a campus publication.

One of those coups was under intense scrutiny at the time of Puliafito’s resignation. In a court battle that is still playing out, the University of California filed suit in July 2015 against USC over its poaching of a leading Alzheimer’s disease researcher.

Puliafito was the self-described “quarterback” of efforts to land UC San Diego professor Paul Aisen, a star in the state university system.

Curing Alzheimer’s is a top priority for government agencies and pharmaceutical companies, and Aisen’s lab was overseeing groundbreaking research, including drug trials at 70 locations around the world. More than $340 million in funding was expected to flow to his lab, according to court records.

UC contended in its suit that its private school rival went beyond the bounds of academic recruiting by targeting professors and labs based on grant funding. The suit accused USC of civil conspiracy, aiding and abetting breach of fiduciary duty and other misconduct.

USC denied any wrongdoing and countersued for defamation and other claims. At the time Puliafito stepped down, UC had yet to question him under oath.

A UC lawyer deposed the former dean in September 2016, and asked about his resignation. A USC attorney objected to the question as “vague” and “overbroad.” Puliafito ultimately answered that he had a “unique opportunity” to work in private industry and that he was on sabbatical from his faculty position.

He had accepted, in April 2016, a position as chief of strategic development at Ophthotech, a New York pharmaceutical company run by friends Puliafito had known since his time at Harvard. The job did not last. The company announced in December that a drug it had been developing failed in clinical trials.

Puliafito, along with 80% of the workforce, was laid off, a company spokeswoman said.

He continues to represent USC in public. On Saturday, he spoke at a Keck-sponsored program at the Langham Huntington Hotel in Pasadena — one of the hotels Sarah Warren said she frequented with him.

Hitler’s charisma, demagoguery, and ability to mobilize Germany behind him have been much written about and discussed. His failed attempt to fight a war on two fronts, and making the same mistake as Napoleon—invading Russia, have also been topics exhausted by scholars and armchair historians alike. But new revelations, such as the fact that the Fuhrer had a micropenis, are changing completely how we view the Second World War.

A 47-page dossier reveals that the rise of Nazi Germany was fueled by drug use. Hitler himself was taking 74 separate drugs, including a powerful opioid, and what we would consider today methamphetamine (crystal meth). The US military report, developed over the course of the war, outlines a number of different substances ingested by the Fuhrer including morphine, barbiturates, tranquilizers, and even bull’s semen.

The bull’s semen was supposed to restore the Fuhrer’s libido in to keep up with his much younger girlfriend, and to make him appear energetic and masculine before the populace. The other drugs were to help alleviate a range of issues from stomach cramps to perhaps, what some historians believe were the symptoms of bipolar disorder.

German writer Norman Ohler covers drug use in Nazi Germany in his new book, The Total Rush (Der Totale Rausch). In America, its entitled Blitzed. The book was a huge success in Germany and has since been translated into 18 languages. According to Ohler, though drugs played a pivotal role, historians overlooked it due to little interest in Hitler’s personal physician, Dr. Theodor Morell.

Ohler’s friend Alexander Kramer, who owns a vast collection of books and memorabilia from the war period and earlier, was the first to tell Ohler about the role narcotics played. Ohler said he knew immediately it would be the subject of his next book. Though he is not an historian, Third Reich expert Hans Mommsen, now deceased, aided the author in his quest. Ohler spent years in archives to piece the story together.

It all begins during the Weimar Republic, and the rise of Hitler. His inner circle lionized him, portraying him as a superior man in mind and body, who never ate meat, never touched drugs or alcohol, or even women. In 1933 when he rose to power, all intoxicating drugs were banned. Addicts were soon executed by the state or sent off to the camps.

Dr. Fritz Hauschild in Berlin developed what was first known in Germany as methyl-amphetamine. In 1937 the company he worked for expressed the hopes of using it to become a rival of Coca Cola. By 1938, the drug became pervasive and available without a prescription. Soon, almost everyone in Germany was using the drug, known as Pervitin, to boost confidence, energy, and attitude.

As ubiquitously as coffee today, it was regarded in much the same way. Housewives ate Pervitin-laced chocolates which allow them to get housework done in a jiffy and even helped them lose weight. Though health and fitness were upheld as a supreme cultural value, the populace and their leader were all in actuality, smashed on drugs.

It was Dr. Otto Ranke, the director of the Institute for General and Defense Physiology, who decided Pervitin was a good way to help soldiers avoid exhaustion. It allowed them to remain awake for long periods, march for miles, and fight in terrifying conditions fearlessly. Before invading France in 1940, Nazi soldiers were instructed to take tablets of Pervitin throughout the day and night. The invasion of Poland was also fueled by meth.

Although Ohler said his mentor told him never to rely on just one cause, the author says the blitzkrieg was utterly dependent on Pervitin. Otherwise, Hitler’s forces could have never swept through Europe as quickly as they did. Records indicate that 35 million tablets were distributed in 1940 over a span of four months, to fuel the western offensive. The idea was to turn ordinary men into superhuman machines.

There is still argument today over whether or not certain drugs improve or impede a soldier’s performance. The side effects of Pervitin were irrational behavior, hallucinations, and enraged outbursts. The Nazis weren’t alone. Many other armies used amphetamines to fight off fatigue. Dexedrine was used by the British and Americans, while the Japanese had their own form of speed.

As the war raged on, Hitler began relying on his doctor more and more, whom was distrusted and loathed by the rest of his inner circle. Dr. Morell meanwhile relied on the Fuhrer for his position. In 1941 Hitler came down with a terrible illness. Though Morell had been famous for vitamin injections, it was clear that these were not going to cut it.

Animal hormones and a series of medications were attempted. Finally, the physician settled on Eukodal, a wonder drug which we would call Oxycodone today. Soon, one of the world’s most famous villains was receiving several injections of Eukodal per day, and combining them with a host of other drugs, including cocaine, which had been prescribed to help with an ear condition endured on the eastern front. The drug cocktail, particularly Eukodal, made Hitler feel invincible, even when it became clear, by 1944, that Germany was losing. His generals frantically appealed to him to change tactics. But Eukodal made him feel powerful, euphoric, and in control, and so he decide to plod along, undeterred.

Late in the war, the factories that made Germany’s drugs were bombed out by the Allies. By early 1945, the Fuhrer was in a state of fevered withdrawal. According to Ohler, the world’s most infamous fascist spent his final days in his bunker, drowning in a hellish state of withdrawal.

Ohler doesn’t think Hitler’s personal physician purposely turned him into an addict, though it is possible. But it’s just as likely that the Fuhrer himself was the driving force, imbued with an addictive personality. Either way, in the fall of 1944, Hitler removed Morell. But by then, it was too late. The Fuhrer took his own life. Morell meanwhile died not too long after the war a sad and broken figure, discarded by history. Ohler portrays him as a tragic figure, a mere opportunist caught up in the forces of his time, while others see him as an out-and-out scoundrel. Regardless of his intentions, his methods seem to have contributed to the downfall of the Third Reich.